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Germani A.,Laboratory of Signal Dependent Transcription | Matrone A.,Laboratory of Signal Dependent Transcription | Grossi V.,Cancer Genetics Laboratory | Peserico A.,Laboratory of Signal Dependent Transcription | And 10 more authors.
Cancer Letters | Year: 2014

Chemoresistance is a major obstacle to effective therapy against colorectal cancer (CRC) and may lead to deadly consequences. The metabolism of CRC cells depends highly on the p38 MAPK pathway, whose involvement in maintaining a chemoresistant behavior is currently being investigated. Our previous studies revealed that p38α is the main p38 isoform in CRC cells. Here we show that p38α pharmacological inhibition combined with cisplatin administration decreases colony formation and viability of cancer cells and strongly increases Bax-dependent apoptotic cell death by activating the tumor suppressor protein FoxO3A. Our results indicate that FoxO3A activation up-regulates transcription of its target genes (p21, PTEN, Bim and GADD45), which forces both chemosensitive and chemoresistant CRC cells to undergo apoptosis. Additionally, we found that FoxO3A is required for apoptotic cell death induction, as confirmed by RNA interference experiments. In animal models xenografted with chemoresistant HT29 cells, we further confirmed that the p38-targeted dual therapy strategy produced an increase in apoptosis in cancer tissue leading to tumor regression. Our study uncovers a major role for the p38-FoxO3A axis in chemoresistance, thereby suggesting a new therapeutic approach for CRC treatment; moreover, our results indicate that Bax status may be used as a predictive biomarker. © 2013 Elsevier Ireland Ltd.


Simonatto M.,Epigenetics and Regenerative Medicine | Simonatto M.,Sanford Burnham Institute for Medical Research | Simonatto M.,Italian National Cancer Institute | Marullo F.,Epigenetics and Regenerative Medicine | And 9 more authors.
Cell Death and Differentiation | Year: 2013

Previous works have established a unique function of MyoD in the control of muscle gene expression during DNA damage response in myoblasts. Phosphorylation by DNA damage-activated ABL tyrosine kinase transiently inhibits MyoD-dependent activation of transcription in response to genotoxic stress. We show here that ABL-MyoD signaling is also an essential component of the DNA repair machinery in myoblasts exposed to genotoxic stress. DNA damage promoted the recruitment of MyoD to phosphorylated Nbs1 (pNbs1)-containing repair foci, and this effect was abrogated by either ABL knockdown or the ABL kinase inhibitor imatinib. Upon DNA damage, MyoD and pNbs1 were detected on the chromatin to MyoD target genes without activating transcription. DNA damage-mediated tyrosine phosphorylation was required for MyoD recruitment to target genes, as the ABL phosphorylation-resistant MyoD mutant (MyoD Y30F) failed to bind the chromatin following DNA damage, while retaining the ability to activate transcription in response to differentiation signals. Moreover, MyoD Y30F exhibited an impaired ability to promote repair in a heterologous system, as compared with MyoD wild type (WT). Consistently, MyoD-null satellite cells (SCs) displayed impaired DNA repair that was rescued by reintroduction of MyoD WT but not by MyoD Y30F. In addition, inhibition of ABL kinase prevented MyoD WT-mediated rescue of DNA repair in MyoD-null SCs. These results identify an unprecedented contribution of MyoD to DNA repair and suggest that ABL-MyoD signaling coordinates DNA repair and transcription in myoblasts. © 2013 Macmillan Publishers Limited All rights reserved.


Chiacchiera F.,Laboratory of Signal Dependent Transcription | Grossi V.,Laboratory of Signal Dependent Transcription | Cappellari M.,Laboratory of Signal Dependent Transcription | Peserico A.,Laboratory of Signal Dependent Transcription | And 9 more authors.
Cancer Letters | Year: 2012

We recently demonstrated that p38α is required to maintain colorectal cancer (CRC) metabolism, as its inhibition leads to FoxO3A activation, autophagy, cell death, and tumor growth reduction both in vitro and in vivo. Here we show that inhibition of p38α is followed by TRAIL-mediated activation of caspase-8 and FoxO3A-dependent HER3 upregulation with consequent overactivation of the MEK-ERK1/2 survival pathway. p38α and MEK combined inhibition specifically induces apoptosis by enabling TRAIL signaling propagation through t-Bid and caspase-3, and fosters cell death in CRC cells and preclinical mouse models. Current MEK1-directed pharmacological strategies could thus be exploited, in combination with p38α inhibition, to develop new approaches for CRC treatment. © 2012 Elsevier Ireland Ltd.


PubMed | Italian Institute of Technology, University of Bari, Cancer Genetics Laboratory, Animal Care Facility and Laboratory of Signal Dependent Transcription
Type: Journal Article | Journal: Cancer letters | Year: 2014

Chemoresistance is a major obstacle to effective therapy against colorectal cancer (CRC) and may lead to deadly consequences. The metabolism of CRC cells depends highly on the p38 MAPK pathway, whose involvement in maintaining a chemoresistant behavior is currently being investigated. Our previous studies revealed that p38 is the main p38 isoform in CRC cells. Here we show that p38 pharmacological inhibition combined with cisplatin administration decreases colony formation and viability of cancer cells and strongly increases Bax-dependent apoptotic cell death by activating the tumor suppressor protein FoxO3A. Our results indicate that FoxO3A activation up-regulates transcription of its target genes (p21, PTEN, Bim and GADD45), which forces both chemosensitive and chemoresistant CRC cells to undergo apoptosis. Additionally, we found that FoxO3A is required for apoptotic cell death induction, as confirmed by RNA interference experiments. In animal models xenografted with chemoresistant HT29 cells, we further confirmed that the p38-targeted dual therapy strategy produced an increase in apoptosis in cancer tissue leading to tumor regression. Our study uncovers a major role for the p38-FoxO3A axis in chemoresistance, thereby suggesting a new therapeutic approach for CRC treatment; moreover, our results indicate that Bax status may be used as a predictive biomarker.


Peserico A.,Laboratory of Signal dependent Transcription | Chiacchiera F.,Laboratory of Signal dependent Transcription | Grossi V.,Cancer Genetics Laboratory | Matrone A.,Laboratory of Signal dependent Transcription | And 11 more authors.
Cellular and Molecular Life Sciences | Year: 2013

Reduction of nutrient intake without malnutrition positively influences lifespan and healthspan from yeast to mice and exerts some beneficial effects also in humans. The AMPK-FoxO axis is one of the evolutionarily conserved nutrient-sensing pathways, and the FOXO3A locus is associated with human longevity. Interestingly, FoxO3A has been reported to be also a mitochondrial protein in mammalian cells and tissues. Here we report that glucose restriction triggers FoxO3A accumulation into mitochondria of fibroblasts and skeletal myotubes in an AMPK-dependent manner. A low-glucose regimen induces the formation of a protein complex containing FoxO3A, SIRT3, and mitochondrial RNA polymerase (mtRNAPol) at mitochondrial DNA-regulatory regions causing activation of the mitochondrial genome and a subsequent increase in mitochondrial respiration. Consistently, mitochondrial transcription increases in skeletal muscle of fasted mice, with a mitochondrial DNA-bound FoxO3A/SIRT3/mtRNAPol complex detectable also in vivo. Our results unveil a mitochondrial arm of the AMPK-FoxO3A axis acting as a recovery mechanism to sustain energy metabolism upon nutrient restriction. © 2012 Springer Basel.


Grossi V.,Cancer Genetics Laboratory | Liuzzi M.,University of Bari | Murzilli S.,Laboratory of Lipid Metabolism and Cancer | Martelli N.,Laboratory of Lipid Metabolism and Cancer | And 5 more authors.
Cancer Biology and Therapy | Year: 2012

In the search for new strategies to efficiently fight colorectal cancer, efforts are being increasingly focused on targeting regulatory signaling pathways involved in cancer-specific features. As a result, several studies have recently addressed the therapeutic potential of molecularly-targeted drugs capable of inhibiting the activity of protein kinases involved in relevant signaling cascades. Here we show that simultaneous inhibition of the DFG-in and DFG-out conformations of p38α by means of type-I and type-II inhibitors is beneficial to impair more efficiently its kinase activity. Moreover, we found that SB202190 (type-I) and sorafenib (type-II) synergize at the molecular and biological level, as co-treatment with these compounds enhances tumor growth inhibition and induction of apoptosis both in colorectal cancer cell lines and animal models. These results support the need to reconsider sorafenib as a therapeutic agent against colorectal cancer and provide new insights that underline the importance to elucidate the activity of protein kinase inhibitors for the treatment of colorectal carcinoma. © 2012 Landes Bioscience.


Grossi V.,Laboratory of Signal dependent Transcription | Simone C.,Laboratory of Signal dependent Transcription
Journal of Oncology | Year: 2012

Ovarian cancer is sensitive to chemotherapy with platinum compounds; however, the therapy success rate is significantly lowered by a high incidence of recurrence and by the acquisition of drug resistance. These negative outcomes mainly depend on altered apoptotic and drug resistance pathways, determining the need for the design of new therapeutic strategies to improve patient survival. This challenge has become even more critical because it has been recognized that hindering uncontrolled cell growth is not sufficient as the only curative approach. In fact, while current therapies are mostly conceived to impair survival of highly proliferating cells, several lines of research are now focusing on cancer-specific features to specifically target malignant cells with the aim of avoiding drug resistance and reducing adverse effects. Recently, great interest has been generated by the identification of metabolic reprogramming mechanisms occurring in cancer cells, such as the increase in glycolysis levels. In this light, pharmacologic manipulation of relevant pathways involved in cancer-specific metabolism and drug resistance could prove an effective approach to treat ovarian cancer patients. Copyright 2012 Valentina Grossi and Cristiano Simone.


Simone C.,Laboratory of Signal Dependent Transcription | Peserico A.,Laboratory of Signal Dependent Transcription
Journal of Biomedicine and Biotechnology | Year: 2011

The balance between protein acetylation and deacetylation controls several physiological and pathological cellular processes, and the enzymes involved in the maintenance of this equilibriumacetyltransferases (HATs) and deacetylases (HDACs)have been widely studied. Presently, the evidences obtained in this field suggest that the dynamic acetylation equilibrium is mostly maintained through the physical and functional interplay between HAT and HDAC activities. This model overcomes the classical vision in which the epigenetic marks of acetylation have only an activating function whereas deacetylation marks have a repressing activity. Given the existence of several players involved in the preservation of this equilibrium, the identification of these complex networks of interacting proteins will likely foster our understanding of how cells regulate intracellular processes and respond to the extracellular environment and will offer the rationale for new therapeutic approaches based on epigenetic drugs in human diseases. Copyright © 2011 Alessia Peserico and Cristiano Simone.


Chiacchiera A F.,Laboratory of Signal dependent Transcription | Simone C.,Laboratory of Signal dependent Transcription
Cell Cycle | Year: 2010

FoxO proteins are an evolutionarily conserved subfamily of transcription factors involved in tumor suppression, regulation of energy metabolism and development in several tissues, and are mainly regulated by phosphorylation- dependent nuclear/cytoplasmic shuttling. The transcriptional activity of FoxO3A, one of the four members of the family, is further modulated by AMPK, one of the key regulators of cellular metabolism, which basically shifts cell machinery from energy-consuming to energy-producing pathways. We recently demonstrated that the AMPK/FoxO3A energy sensor pathway is still inducible in human cancer cells in response to metabolic stress, as it becomes activated in colorectal and ovarian cancer cells in response to the inhibition of p38α. Activation of the FoxO3A transcriptional program initially induces autophagy as an attempt to retain energy to survive, whereas under persistent stress conditions it triggers autophagic cell death. In this review, we focus on the connections between AMPK and FoxO3A, describing their central role as modulators of fundamental processes such as stress resistance, cell metabolism, autophagy and cell death, and highlighting the therapeutic potential of pharmacological modulation of the AMPK-FoxO3A axis. © 2010 Landes Bioscience.


PubMed | Laboratory of Signal dependent Transcription
Type: | Journal: Journal of oncology | Year: 2012

Ovarian cancer is sensitive to chemotherapy with platinum compounds; however, the therapy success rate is significantly lowered by a high incidence of recurrence and by the acquisition of drug resistance. These negative outcomes mainly depend on altered apoptotic and drug resistance pathways, determining the need for the design of new therapeutic strategies to improve patient survival. This challenge has become even more critical because it has been recognized that hindering uncontrolled cell growth is not sufficient as the only curative approach. In fact, while current therapies are mostly conceived to impair survival of highly proliferating cells, several lines of research are now focusing on cancer-specific features to specifically target malignant cells with the aim of avoiding drug resistance and reducing adverse effects. Recently, great interest has been generated by the identification of metabolic reprogramming mechanisms occurring in cancer cells, such as the increase in glycolysis levels. In this light, pharmacologic manipulation of relevant pathways involved in cancer-specific metabolism and drug resistance could prove an effective approach to treat ovarian cancer patients.

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